Human herpesvirus 8 (HHV-8/KSHV) is etiologically associated with Kaposi's Sarcoma (KS), primary effusive lymphoma (PEL), and multicentric Castleman disease (MCD). KS is a chronic inflammation associated angioproliferative malignancy characterized by a heterogeneous population of spindle- shaped endothelial cells, inflammatory cells, cytokines, growth factors and angiogenic factors, whereas PEL and MCD are proliferative B cell malignancies. Several lines of evidence demonstrate that HHV-8 binding and entry into the target cell as well as the expression of viral proteins induce secondary messengers and signaling pathways that are essential for efficient infection and establishment of latency and pathogenesis. Available treatment strategies to control HHV-8 infection associated malignancies are limited and of low efficacy. Hence, there is a vital requisite for designing therapies that target viral infection and tumor formation. We theorize that one of the secondary messages induced during HHV-8 infection is the production of reactive oxygen species (ROS) and subsequent activation of the transcription factor Nrf2 (NF-E2- related factor 2). Our exciting preliminary data demonstrate an increase in ROS production and the activation of Nrf2 after primary infection and in latently infected cells. Since little is known about the induction of ROS and Nrf2 in infected cells, we propose to characterize the HHV-8 induced ROS and Nrf2 and decipher their roles in HHV-8 infection. The central hypothesis is that HHV-8 binding/entry during primary infection and subsequent latent gene expression elevates ROS that activates Nrf2 which plays major roles in the HHV-8 life cycle and pathogenesis. We propose: 1- To decipher the mechanism of ROS production and Nrf2 activation by HHV-8. 2- To decipher the role of ROS and Nrf2 in HHV-8 infected cells. Our studies proposed under these two aims are expected to identify the mechanism and consequences of ROS and Nrf2 activation in HHV-8 infection, inflammation and cell survival. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to demonstrate that the activation of ROS and Nrf2 pathways are critical for HHV-8 biology and pathogenesis. The knowledge gained from these studies will greatly increase our understanding of how ROS production and Nrf2 activation are induced by HHV-8 and the consequences on the virus infectivity, viral life cycle as well as on the cell survival and inflammatory processes. The resuls could potentially lead to the development of pharmacologic strategies to control HHV-8 infection and the associated malignancies.